Bioreactors, which are typically chambers in which a cell culture is grown, have been produced in many forms. Frequently, bioreactors are used to grow a mammalian cell culture in which the cells produce an extracellular component, such as an antibody or recombinant protein. Bioreactors are also used for virus production. A separation process is performed in order to concentrate and purify the desired component from the bioreactor, which may, for example, be useful as a therapeutic or diagnostic agent. Bioreactors are complex mechanical devices that provide mainly the mixing and gasification of liquids to grow a biological culture; this step is followed by several additional unit processes including the separation of cells, filtration to reduce the volume of nutrient medium, loading onto chromatography columns and several steps of purification. In recent years, there has been a raised awareness to produce many biological products on a short turn around time, particularly as it relates to the products needed to combat terrorism-related needs; this also includes the need to quickly develop and manufacture vaccines and antibodies. Current methods require availability of clean rooms, large capital investment and lengthy and tedious processes to manufacture these products. There is a great unmet need for creating a bioreactor system that will be capable of producing biological products under the most optimal conditions, be able to combine all steps of biological product manufacturing within the same container and be of the lowest cost to own and operate. Additionally, this will be a closed system that can be installed and used anywhere without the need for clean rooms and where the operators will be protected by the product as well. Such an invention will change the course of drug discovery and manufacturing, making it possible to provide life-saving new drugs to mankind at an affordable cost. Independently, the invention will serve many critical needs of counter-terrorism operations as well as epidemic control.
Mixing and gasification are the main functions that every available bioreactor performs today. Generally, separate mechanical devices are provided to perform these functions but in some instances, bubble reactors are used where the mass of air moving upwards provides the mixing function as well. It is impossible to ideally combine the two functions in one—using gasification to mix fluids because of the imbalance between the gasification requirements and the mixing functionality. Many of the reactions in a bioreactor need to be performed in an environment that will protect the product from the environment and the personnel from the product; this requires establishment of clean room facilities that can cost millions of dollars to construct and validate. Additionally, many steps required in the purification of biological drugs are performed independently of the phase when the biological product is produced such as from CHO cells that secrete the product or bacteria that produce it as inclusion bodies.
A system that combines all steps in the manufacturing of biological products, from growing cells to secrete them to separating the biological product and purifying it within the same container that remains closed during the entire operation will change the way biological drugs are developed and manufactured. This will be most suitable for situations where a product needs to be manufactured quickly such as in counter-terrorism operations as well as when protecting the public from epidemics since this system will allow a quick deployment of the manufacturing. The ability to manufacture biological drugs in an uncontrolled environment will make it possible to manufacture a variety of products at a fraction of their current cost, increase their availability and the protection provided by the enclosed systems will permit manufacture of biological products that could not otherwise be done safely.
The aspect about combining the harvesting and purification of drugs within the bioreactor is novel and a disruptive technology. While the bioreactors are exclusively used for the purpose of growing bacteria or other cells, their role can be expanded to include other processes that can be completed within the bioreactor. There is an unmet need to develop a bioreactor for expressing and separating a biological product from other components in the nutrient medium, combining the steps of expressing and separating within the bioreactor by binding the biological product with a chromatography media within a bioreactor, discarding the nutrient medium and eluting the biological product as a concentrated solution; this will eliminate at least three steps in the separation and purification of biological products—filtration or centrifugation to remove cell culture, perform ultrafiltration for volume reduction, and purification of biological product by selective elution from the bioreactor; the last use makes the bioreactor a chromatography column.
The time and cost-consuming steps of filtration, chromatography and purification slow down the manufacturing process and add substantial capital cost requirement to establish cGMP-grade manufacturing operations, particularly in a clean room environment.